Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, two lymphoid malignancies that primarily strike young healthy adults, classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL), are largely defined by their morphologic appearance and physical location. Current treatments for cHL and MLBCL are based on empiric combinations of available chemotherapeutic agents rather than targeted approaches to disease-specific survival pathways. The most common subtype of cHL, nodular sclerosing Hodgkin lymphoma (NSHL), and MLBCL share certain biological and clinical features. Both diseases commonly present as local/mediastinal tumors that spread to adjacent, rather than distant, nodes and organs. One of the defining paradoxical features of primary cHLs is the presence of an extensive, largely ineffective, inflammatory infiltrate. Primary MLBCLs include scattered infiltrating lymphocytes and variable degrees of sclerosis; however, little is known about an associated host anti-tumor immune response. We have integrated the comprehensive transcriptional profiles and whole-genome HD SNP array data in cHL and MLBCL and identified chromosome 9p24.1 amplification and the associated overexpression of PD-1 ligands and their inducer, JAK2, as major features of these diseases. We hypothesize that: 1) the disease-specific genetic alteration and overexpression of PD-1 ligands in cHL and MLBCL induces PD-1 signaling, exhaustion of PD-1 receptor+ tumor-infiltrating T cells and tumor immune escape; and 2) JAK2 further induces PD-1 ligand expression and augments tumor cell proliferation. As a consequence, molecular analyses of 9p24, PD-1 ligand and JAK2 amplification will likely have prognostic significance and the PD-1 pathway and JAK2 will represent rational therapeutic targets in these diseases. Importantly, immune evasion mediated by the PD-1/PD-1 ligand axis can be inhibited with neutralizing PD-1 receptor monoclonal antibodies and JAK2 signaling can be abrogated with clinical grade small molecules. For these reasons, we propose the following specific aims: 1.0 Assess the frequency and prognostic significance of 9p24 amplification and increased PD-1 ligand and JAK2 expression in patients with cHL and MLBCL; 2.0 Elucidate the bases for relative differences in PD-L1 and PD-L2 expression in cHL and MLBCL; 3.0 Evaluate the efficacy of PD-1 ligand/PD-1 receptor blockade in patients with cHL and MLBCL; and 4.0 Assess the consequences of chemical JAK2 inhibition in cHL and MLBCL. The proposed studies will translate the comprehensive genomic analyses of cHL and MLBCL into robust clinically relevant diagnostic and prognostic signatures and a targeted, personalized approach to treatment.